In this specification, where a document, act or item of knowledge is referred to or discussed, this reference or discussion is not to be taken as an admission that the document, act or item of knowledge was at the priority date: part of common general knowledge; or known to be relevant to an attempt to solve any problem with which this specification is concerned.
The major objective in drug delivery is to obtain an appropriate biological effect at a desired site of action. The choice of carrier can be critical to the efficacy of a topically delivered pharmaceutical or pharmacologically active compound. Bioactivity of a pharmaceutical will however, be sub-optimal if it does not possess the correct physiochemical properties to allow release of the biologically active form, from the formulation to the target site of action after passage across the skin.
Drug Transfer through the Skin
When a drug is released from a formulation it will first partition into the outer lipids of the stratum corneum. The degree of absorption will depend primarily upon solubility of the drug into these lipids and partition co-efficient of the drug between the skin and the formulation. A simple method for maximizing this is to choose formulation components that allow the drug dose to reach its solubility limit. Ostrenga et al. demonstrated this principle by improving solubility and partition characteristics of two corticosteroids through manipulating the formulation ratio of water and propylene glycol, demonstrating that the most effective formulations were those that contained adequate propylene glycol to solubilize the maximum drug concentration in the finished pharmaceutical product (Ostrenga J. Steinmetz C, Poulsen B. Significance of vehicle composition 1. Relationship between topical vehicle composition, skin penetrability, and clinical efficacy. J. Pharm. Sci. 1971; 60:1175-1179).
It is also reported that supersaturated systems provide thermodynamic activity greater than unity that enhances skin penetration of drugs. A drug solvent system using a mixture of volatile and non-volatile solvents as vehicles, where the volatile compounds evaporate from the skin, can create a supersaturated solution on the skin surface and stimulate drug absorption. It is thought that some transdermal patch delivery systems have the ability to absorb water from the skin increasing thermodynamic activity of a drug creating a supersaturated solution thereby promoting its passage through the skin. One of the major problems with use of mixed volatile and non volatile delivery systems however, is the difficulty in creating systems that are reproducible, as the rate and degree of volatile evaporation will depend, to a large extent upon ambient conditions during application. Variability in absorption kinetics causes fluctuations in drug delivered and unreliable clinical efficacy.
When a suitable solvent system cannot be identified suspensions may be used. In these formulations, particle size of the incorporated drug compound can significantly influence effective absorption. This was demonstrated by Barrett et al. using a variety of fluocinolone acetonide formulations (Barrett C W, Hadgraft J W, Caron G A, Sarkany I. The effect of particle size and vehicle on the percutaneous absorption of fluocinolone acetonide. Brit. J. Dermatol 1965; 77:576-78). The formulations were applied to forearm skin of volunteers and degree of vasoconstriction measured. The effect was greatest in those formulations using micronized drug that had been taken into solution with propylene glycol. It was concluded that solubility and partition characteristics of a drug were dearly important parameters in formulating to promote skin absorption. In theory this means that drugs with good oil and water solubility and balanced partition coefficient, will better penetrate the skin.
Modern drugs typically do not have optimal solubility characteristics, and this is currently quantified by use of a solubility parameter. This has been estimated to be approximately for the skin, so drugs with solubility parameters similar to this may be expected to be freely soluble creating a large concentration gradient across the skin or high partition co-efficient. The importance of this is evident in an analysis of skin permeability data by Potts and Guy (Potts R O, Guy R H. Predicting skin permeability. Pharm. Res. 1992; 9:663-669) who examined the permeability of 90 compounds in aqueous solution and determined that permeability coefficient (Kp) through the skin was related to their octanol-water partition coefficient and the molecular weight in the following relationship:Log Kp (cm s−1)=−6.3+0.71 log P−0.0061 MW (r2=0.69)
This emphasizes the importance of solubility and partition coefficient, but like many mathematical structure activity relationships, results in a 2 dimensional answer to a three dimensional problem. For example, flux through the skin using this equation results in a parabolic dependency on the partition coefficient which is still unclear. If a true linear concentration gradient existed then the higher the concentration gradient, the higher the drug absorption. The fact that the relationship is not linear suggests that physical limits exist, such as the number of pores in the skin or physiochemical forces other than solubility, dissolution and dispersion which also act to facilitate membrane transport. It has been suggested that at high log P (a highly lipophilic compound), the transfer out of the stratum corneum is rate limiting or that drugs with high log P values generally have poor aqueous solubility. This means that lipid soluble drugs tend to stay in the phospholipid membrane because by nature they are lipophilic, that is, the drugs are trapped in the skin and not released to the target site.
Based on the equation and the accompanying assumption that drugs are transported across skin by virtue of a concentration gradient, it is suggested that drugs with log P in the range of 1 to 3 are more likely to diffuse through the skin. However, this simply serves to identify drugs that may move easily through the skin. This does not help to improve the transport of poorly soluble, highly lipophilic drugs.
Skin Enhancers
Many modern drugs are highly lipophilic so skin enhancers and various formulation techniques have been developed to improve their absorption through the skin. Skin enhancers typically function to modify structure especially of the stratum corneum by dissolving or interfering with the lipid matrix to improve permeability of drug compounds. Examples include compounds like capric acid, oleic acid, azone, decylmethyl sulfoxide and hydroxy cinnamates. Dermal absorption of progesterone for example increases by 143% when the stratum corneum is delipidized. The enhancement increases to 843% when the stratum corneum is totally eliminated. With such aggressive modification, commonly reported problems with repeated use of such systems include contact dermatitis, reddening of the skin, itching and burning that requires movement of the patch or application of the drug, around the body to prevent local irritation. The reddening is said to disappear within hours of removing the patch. But concern has been raised with respect to long term risk and safety of use of this type of transdermal delivery system, mainly because increased drug permeability is achieved at the cost of damaging a fundamentally important protective layer of the skin.
A study by Morgan, T M. et al (1998). “Enhanced transdermal delivery of sex hormones in swine with a novel topical aerosol” J Pharm. Sci. 87(10): 1219-1225 investigated the transdermal delivery of testosterone and estradiol in pigs using a novel metered dose topical aerosol containing a penetration enhancer padimate O. The authors claim that the dose system provides flexibility and can be moved around to provide a greater surface area of application. However, metered dose devices require co-ordination and manual dexterity for efficient use.
There have been a number of attempts to develop drug delivery systems which are less aggressive to the skin, however none of these attempts have provided commercially acceptable products. For example:                U.S. Pat. No. 6,479,540 discloses use of a tocol based delivery system to solublize charged amphophilic and water soluble pharmaceutically active compounds. The patent teaches that the charged esters of tocopherol, such as phosphate, succinate, aspartate and glutamate form ion pairs with suitable drug substrates which in turn associate with the tocol emulsion. The formulation thus renders the active compound to be much more lipophilic and incorporated in miscelles that may permit better transport through mucosal membranes.        U.S. Pat. No. 5,583,105 discloses use of tocol and tocol derivatives including tocopherol polyethylene glycol 1000 succinate (TPGS) as solvents to dissolve certain drugs at high enough concentrations to be therapeutically useful. Emulsions and emulsification with solublizers have a long history in drug delivery art. TPGS is used as a pharmaceutically acceptable water miscible solubilizer and there is no teaching regarding any other interaction between TPGS with lipophilic pharmaceuticals.        International patent application WO 96/21440 discloses a method for improving bioavailability of a medicinal agent by covalent attachment of inositol phosphate and biphosphonate molecules. The resulting conjugates are said to have increased water solubility relative to the unconjugated agent.        
The art of efficient topical drug delivery therefore requires that the drug be both soluble in the aqueous biological medium and in an appropriate form to permit transport of either individual drug molecules or very small aggregates of the drug molecules. This aim may be difficult to realise with drugs that are lipid soluble and not significantly water soluble, unless the delivery system is recognised by normal membrane transport systems. Such drug molecules have hydrophobic regions that form large aggregates in the high dielectric constant water rich medium where transport occurs.
A suitable carrier capable of topically delivering a broad range of pharmaceuticals or pharmacologically active compounds and improving absorption of the pharmaceutical or pharmacologically active compound in the targeted area without damaging the skin is therefore required.